The effect of previous nitrate therapy on vascular responses to endothelin-1 (ET-1) and NO was investigated in human internal mammary artery (IMA) in vitro. Cumulative concentration–response curves to ET-1 were constructed in rings of IMA and the data grouped into IMA from patients given nitrates prior to the bypass graft operation (nitrate group) and IMA from patients who were not prescribed nitrates (control group). No significant differences were observed between the two groups, either in EC 50 value [ P >0.05; 3.5nM (2.4–5.3nM; 95% confidence interval) and 4.8 (2.2–10nM), nitrate and control groups respectively] or E max ( P >0.05; 78±7.5% and 85±9.5%, nitrate and control group respectively). No significant differences in concentration–response curves to the NO-donor diethylamine NONOate (DEA/NO) in rings of IMA pre-constricted with 10nM ET-1 were observed between control and nitrate groups [ P >0.05; EC 50 values 0.59 (0.21–1.7) µ M and 0.17 (0.03–0.87) µ M; E max 110±5.7% and 112±4.5%, nitrate and control groups respectively]. Concentration–response curves to DEA/NO constructed in normal coronary artery were not significantly different from those in coronary artery obtained from patients with ischaemic heart disease (IHD) [ P >0.05; E max 124±11% and 138±20%; EC 50 0.08 (0.02–0.30) µ M and 0.23 (0.02–24) µ M, normal and IHD respectively]. These data indicate that nitrate therapy does not induce long-term changes in the ET signalling pathway. Furthermore, the tolerance to nitrate therapy is likely to be because of impaired bio-transformation of the drug rather than reduced sensitivity of the media to NO. The similar responses to DEA/NO in normal and atherosclerotic coronary artery suggests that the reduced vasodilator responses in IHD is because of a dysfunctional endothelium and is not mediated by changes in the NO signalling pathway of the smooth muscle.

1. The aim of the present study was to investigate the effects of exercise and of sublingual glyceryl trinitrate on the pattern of blood flow, as studied by Doppler ultrasound, in internal mammary artery grafts performed to relieve severe stenosis of the left anterior descending coronary artery. The accessibility of the graft to transcutaneous ultrasound examination allows the effects of exercise and nitrate administration on coronary blood flow to be studied non-invasively. 2. Angina-free patients with left internal mammary to left anterior descending coronary artery grafts were studied using transcutaneous duplex ultrasound at rest, after leg exercise and after sublingual administration of 0.5 mg or 1 mg of glyceryl trinitrate. 3. Resting graft blood flow showed a biphasic pattern, with forward flow in both systole and diastole. Exercise caused an increase in time-averaged velocity of graft blood flow from 17.3 (3.3) to 24.0 (7.2) cm/s ( P = 0.001), and of calculated volume flow from 44.7 (3.08) to 59.8 (5.89) ml/min ( P = 0.002). Diastolic peak velocity increased from 36.1 (9.9) cm/s to 46.8 (16.2) cm/s ( P = 0.04), while peak systolic velocity was unchanged. Nitrate administration caused a fall in systolic and diastolic blood pressure and an increase in heart rate; graft flow was maintained [time-averaged velocity 18.3 (6.2) cm/s before and 16.7 (5.7) cm/s after 500 μg of glyceryl trinitrate], but systole was shortened and the proportion of blood flow in diastole increased [systolic/diastolic flow ratio 0.558 (0.139) before and 0.374 (0.156) after 500 μg of glyceryl trinitrate, P = 0.01]. 4. Doppler ultrasound examination of internal mammary artery to coronary artery grafts is one of the few ways in which physiological changes in coronary flow can be assessed non-invasively in human subjects. Exercise-induced increases in graft flow involve both increased graft distension in systole and increased run-off in diastole — the elasticity of internal mammary artery grafts may be important in sustaining an exercise-induced increase in graft flow. Limitations of the technique include the difficulty of accurately measuring graft diameter, the possibility of flow through persisting connections between the graft and chest wall vessels and competing flow from the native circulation.

1. Concentrations of ascorbic acid (ascorbic and dehydro-ascorbic; A+D; measured by the 2,4-dinitrophenylhydrazine method) of nearly three times those of plasma are present in gastric juice samples from patients with normal gastric histology. 2. A significant reduction in gastric juice ascorbic acid (A+D) was observed in patients with chronic gastritis. This reduction in concentration was independent of the grade of gastritis. 3. Concentrations of ascorbic acid (A+D) in gastric biopsy specimens were consistently higher in the antrum than in the body of the stomach. 4. These data demonstrate that considerable quantities of ascorbic acid (A+D) are normally ‘secreted’ into the stomach. 5. Ascorbic acid (ascorbic only; A; measured by h.p.l.c.) was present predominantly in its biologically active form in the patients with normal gastric histology. However, in patients with gastritis, independent of grade, ascorbic acid was present predominantly in its oxidized, biologically inactive form.